Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.88 mg/m³

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

44 mg/m³

Explanation for the modification of the dose descriptor starting point:

Converted oral NOAEL rat (in mg/Kg bw/day) into inhalation NOAEC human (in mg/m³) by using a default respiratory volume for the rat corresponding to the daily duration of human exposure, followed by a correction for differences in absorption between routes, and a correction for differences in inhalation absorption between rats and humans. For workers an additional correction was applied for the difference between respiratory rates under standard conditions and under conditions of light activity.

Corrected inhalatory NOAEC = oral NOAEL x (1 / sRV_rat) x (ABS_oral-rat/ ABS_inh-human) x (sRV_human/wRV)

= 50 mg/Kg bw/day x (1/0.38 m³/Kg/day) x (1/2) x (6.7 m³(8h) /10 m³(8h))

Corrected inhalatory NOAEC= 44 mg/m³

ABS: Absorption; sRV: standard Respiratory Volume; wRV: worker Respiratory Volume

Note: A default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) introduced in the case of oral-to-inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for differences in duration of exposure:

4

Justification:

The exposure duration of the OECD TG 422 study performed with the test item was up to 63 days for females and 29 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the assessment factor of 4.

AF for interspecies differences (allometric scaling):

1

Justification:

Default assessment factor - allometric scaling factor not applied (page 62, Example B3, of the ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for other interspecies differences:

2.5

Justification:

Default assesment factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for intraspecies differences:

5

Justification:

For workers, as standard procedure for threshold effects, a default assessment factor of 5 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for the quality of the whole database:

1

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.25 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Converted oral NOAEL rat (in mg/Kg bw/day) into dermal N(L)OAEL rat (in mg/Kg bw/day) by correcting for differences in absorption between routes as well as for differences in dermal absorption between rats and humans.

Corrected dermal NOAEL = oral NOAEL x (ABS_oral-rat/ ABS_dermal-rat) x (ABS_dermal-rat/ ABS_dermal-human)

= 50 mg/Kg bw/day x (ABS_oral-rat/ ABS_dermal-human)

= 50 mg/Kg bw/day x (1/1)

Corrected dermal NOAEL = 50 mg/Kg bw/day

Note: Dermal absorption assumed not be higher than oral absorption, therefore no default factor (i.e. factor 1) introduced when performing oral-to-dermal extrapolation (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for differences in duration of exposure:

4

Justification:

The exposure duration of the OECD TG 422 study performed with the test item was up to 63 days for females and 29 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the assessment factor of 4.

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling factor for rats compared to humans (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for other interspecies differences:

2.5

Justification:

Additional factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for intraspecies differences:

5

Justification:

For workers, as standard procedure for threshold effects, a default assessment factor of 5 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for the quality of the whole database:

1

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Acute toxicity

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not required if no acute toxicity hazard leading to classification has been identified.P-Cymene is not acutely toxic following oral or dermal exposure (LD₅₀>2000 mg/Kg bw). No DNELs for acute systemic toxicity are therefore necessary.

Irritation

p-Cymene is not considered to be a primary skin but not eye irritant and is thus not classified as skin or eye irritant under EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. Thus, a no hazard has been identified.

Sensitisation

The sensitisation potential of p-Cymene is well understood and comprises results from a local lymph node assays, a human maximisation test, and a guinea pig open epicutaneous test. The results consistently showed that p-Cymene is not a skin sensitizer.

Repeated dose toxicity

In a key combined repeated dose toxicity with reproduction/developmental toxicity screening study in the rat, the potential effects of repeated oral gavage administration of the test material (p-Cymene; CAS# 99-87-6) on male and female reproductive performance and systemic toxicity were evaluated in accordance with OECD Test Guideline 422 (Envigo CRS, Inc., 2019).

The test material was administered to Sprague-Dawley CD®rats (10 animals/sex/group) were via oral gavage once daily at 0 (corn oil), 50, 100 or 200 mg/Kg/day. P0 males were dosed during the pre-cohabitation, cohabitation and post-mating periods (approximately 35 days) and then euthanized and necropsied. P0 females were dosed during the pre-cohabitation and cohabitation periods and during gestation and lactation through lactation Day 13 for approximately 63 days and then euthanized and necropsied. Parameters evaluated during the study for the P0 animals were: viability, clinical observations, body weights, food consumption, estrous cycling, mating and fertility, parturition and littering, functional assessments including motor activity, clinical pathology (termination), hormoneanalysis, organ weights, macroscopic observations and microscopic pathology.

No test material-related mortalities were observed during the study in males or females at ≤100 mg/Kg/day. No adverse test material-related clinical observations were observed during the study in males at ≤ 200 mg/Kg/day and in females at ≤ 100 mg/Kg/day. In adult (P0) females (except animal no.4572), there were no macroscopic findings considered to be treatment-related. There were no test material-related reductions in the body weights, body weight changes and food consumption in either gender at ≤ 200 mg/Kg/day.

Week 5 hindlimb grip strength was significantly reduced in the 200 mg/Kg/day males. The LD 8 fore limb and the hindlimb grip strength in the 50 and 100 mg/Kg/day female groups and the Week 5 male fore limb grip strength in the 50, 100 and 200 mg/Kg/day dose groups were comparable to control group values. There were no adverse treatment-related haematology, clinical chemistry or coagulation changes observed at ≤ 200 mg/Kg/day. There were no macro- and/or microscopic findings or organ weight changes in the reproductive tract of females at 50, 100, or 200 mg/Kg/day where examined.

Test material-related testicular changes were observed at 200 mg/Kg/day (lower organ weights, germ cell depletion/degeneration, depletion, and/or sperm retention), along with correlative changes in the epididymis that were considered adverse. These changes were considered the likely cause of the total absence of pregnancy among P0 females in the 200 mg/Kg/day dose group. At 100 mg/Kg/day, a marginal degree of sperm retention was observed and this may have contributed to the absence of pregnancy in 60% of P0 females at the mid-dose level.

Elevated liver weights were observed in males at 200 mg/Kg/day (and minimally at 50 and 100 mg/Kg/day) and in females at 50 and 100 mg/Kg/day (no organ weight data for 200 mg/Kg/day females).

Based on the results observed, the NOAEL for P0 males was determined to be 50 mg/Kg/day, based on epididymal and testicular organ weights, testicular germ cell degeneration/depletion and/or sperm retention in the testes and epididymal luminal cell debris and reduced sperm and cribriform changes at 100 or 200 mg/Kg/day. Based on alterations in oestrous cyclicity and morbidity at 200 mg/Kg/day the, NOAEL for P0 females was considered to be 100 mg/Kg/day.

A 14-day repeated dose range-finding toxicity study was conducted to assess the toxicity of the test material (p-Cymene; CAS# 99-87-6) when administered orally to rats (Envigo CRS, Inc., 2018). In this study, the test material was administered via oral gavage (in corn oil) once daily at 0, 50, 150, or 500 mg/Kg/day to Crl:CD(SD) IGS rats (3/sex/dose) for a period of 14 days.

The homogeneity and concentration results for p-cymene dose formulations of all groups were analyzed during the course of the study, and met the specified acceptance criteria. At the end of the treatment period, all surviving animals were euthanized and necropsied. Parameters evaluated during the study were viability, clinical observations, body weights, food consumption, organ weights (liver, spleen and kidney) and macroscopic examination.

One female in the 500 mg/Kg/day dose group (Animal No. 4523) was sacrificed as moribund on study Day 13. This animal was thin and exhibited rapid breathing, decreased activity and hunched posture. There were no macroscopic findings indicative of a gavage accident. The unscheduled death in this 500 mg/Kg/day dose group female was considered likely to be test material-related based on its occurrence in the high-dose group and the presence of test material-related organ weight differences and macroscopic abnormalities in animals surviving to terminal sacrifice at this dose level. Except for this one female in the 500 mg/Kg/day dose group, there were no adverse treatment-related clinical signs observed at any dose level in male or female rats.

Body weights and body weight changes were reduced in the 150 mg/Kg/day dose group females. Body weights, body weight changes and food consumption (females only) were reduced in male and female rats in the 500 mg/Kg/day dose group.

Necropsy and gross pathology revealed one 150 mg/Kg/day male with discoloured lungs and bronchi (dark red area on the right caudal lobe [≤ 1mm, 1 (one)] and stomach (black areas on the glandular mucosa [≤ 1mm, 2-5 (few)], one 150 mg/Kg/day male with discoloured thymus and small epididymides and testes, and two of three males from the 500 mg/Kg/day group had small, soft testes. A single female from the 500 mg/Kg/day group had a small thymus, uterus and cervix.

Fourteen days of oral gavage dosing with p-cymene was associated with organ weight differences in the liver (higher weight at ≥150 mg/Kg/day) and spleen (lower weight at 500 mg/Kg/day) and macroscopic abnormalities in the testes (small size/soft texture at ≥150 mg/Kg/day).

The exact etiology of the organ weight and macroscopic findings could not be determined. Decreased splenic weight and small testicular size can be directly related to test material administration or indirectly (secondary) to stress. The designation of findings as stress-related versus direct toxicity require a weight of evidence approach involving evaluation of multiple endpoints including clinical pathology, macroscopic findings, microscopic findings, organs weights (particularly the spleen, adrenal glands and thymus) as well in-life observations (Everds, NE, Snyder, PW, Bailey KL et al (2013). Interpreting stress responses during routine toxicity studies: a review of the biology impact and assessment. Toxicol Pathol. 41(4):560-614)).

Genetic Toxicity

Adequate information exists to characterise the mutagenicity of p-Cymene. Results of a bacterial mutation assay demonstrate that p-Cymene was not mutagenic to Escherichia coli strain Sd-4-73 under the conditions of the test. When tested using mammalian cells in vitro, in the absence and in the presence of S9 fraction, p-Cymene was inactive in a gene mutation assay (Chinese hamster lung fibroblasts (V79) cells) and in a mammalian chromosome aberration test (human blood lymphocytes).

Reproductive / Developmental Toxicity

In a key combined repeated dose toxicity with reproduction/developmental toxicity screening study in the rat, the potential effects of repeated oral gavage administration of the test material (p-Cymene; CAS# 99-87-6) on male and female reproductive performance and systemic toxicity were evaluated in accordance with OECD Test Guideline 422 (Envigo CRS, Inc., 2019).

The test material was administered to Sprague-Dawley CD®rats (10 animals/sex/group) were via oral gavage once daily at 0 (corn oil), 50, 100 or 200 mg/Kg/day. P0 males were dosed during the pre-cohabitation, cohabitation and post-mating periods (approximately 35 days) and then euthanized and necropsied. P0 females were dosed during the pre-cohabitation and cohabitation periods and during gestation and lactation through lactation Day 13 for approximately 63 days and then euthanized and necropsied. Parameters evaluated during the study for the P0 animals were: viability, clinical observations, body weights, food consumption, estrous cycling, mating and fertility, parturition and littering, functional assessments including motor activity, clinical pathology (termination), hormone analysis, organ weights, macroscopic observations and microscopic pathology.

No test material-related mortalities were observed during the study in males or females at ≤100 mg/Kg/day. No adverse test material-related clinical observations were observed during the study in males at ≤ 200 mg/Kg/day and in females at ≤ 100 mg/Kg/day. In adult (P0) females (except animal no.4572), there were no macroscopic findings considered to be treatment-related. There were no test material-related reductions in the body weights, body weight changes and food consumption in either gender at ≤ 200 mg/Kg/day.

Week 5 hindlimb grip strength was significantly reduced in the 200 mg/Kg/day males. The LD 8 fore limb and the hindlimb grip strength in the 50 and 100 mg/Kg/day female groups and the Week 5 male fore limb grip strength in the 50, 100 and 200 mg/Kg/day dose groups were comparable to control group values.

There were no adverse treatment-related haematology, clinical chemistry or coagulation changes observed at ≤ 200 mg/Kg/day. There were no macro- and/or microscopic findings or organ weight changes in the reproductive tract of females at 50, 100, or 200 mg/Kg/day where examined.

Elevated liver weights were observed in males at 200 mg/Kg/day (and minimally at 50 and 100 mg/Kg/day) and in females at 50 and 100 mg/Kg/day (no organ weight data for 200 mg/Kg/day females).

Treatment-related reductions in male fertility and male fertility index were observed at ≥ 100 mg/Kg/day. There were test material-related testicular changes observed at 200 mg/Kg/day (lower organ weights, germ cell depletion/degeneration, depletion, and/or sperm retention), along with correlative changes in the epididymis that were considered adverse. These changes were considered the likely cause of the total absence of pregnancy among P0 females in the 200 mg/Kg/day dose group. At 100 mg/Kg/day, a marginal degree of sperm retention was observed and this may have contributed to the absence of pregnancy in 60% of P0 females at the mid-dose level.

Test material-related alterations of oestrous cyclicity, including a reduction of the number of animals with all regular cycles and an increase in the number of females with at least one irregular cycle, were observed in the 200 mg/Kg/day dose group females. There were treatment-related reductions in female fertility and female fertility index at ≥100 mg/Kg/day. The number of females that were pregnant were significantly reduced at ≥100 mg/Kg/day dose level.

No litters delivered at 200 mg/Kg/day (the highest dose tested) and treatment-related reductions in litter viability were observed at 100 mg/Kg/day, the highest dose at which litters were delivered. In addition, treatment-related alterations in pup mortality (decreased live birth index and the post-implantation survival index) were observed at 100 mg/Kg/day. Mean pup weights and mean litter weights were reduced in the 100 mg/Kg/day dose group on PND 1. At study termination, T4 values were reduced (0.44 to 0.63 of control) in F1 males only at 100 and 200 mg/Kg/day.

Based on the results observed, the systemic toxicity NOAEL for P0 males was determined to be 50 mg/Kg/day, based on epididymal and testicular organ weights, testicular germ cell degeneration/depletion and/or sperm retention in the testes and epididymal luminal cell debris and reduced sperm and cribriform changes at 100 or 200 mg/Kg/day. Based on alterations in oestrous cyclicity and morbidity at 200 mg/Kg/day the, NOAEL for P0 females was considered to be 100 mg/Kg/day.

The NOAEL for F1 offspring was determined to be 50 mg/Kg/day, based on decreased pup live birth index, decreased post-implantation survival index, decreased pup viability, decreased pup weights and litter weights in the 100 mg/Kg/day dose group on PND 1.

DNEL Worker long-term lnhalation-systemic

Dose descriptor

A NOAEL of 50 mg/Kg bw/d will be used as the starting point.

Modification of dose descriptor

A default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) introduced in the case of oral-to-inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation.

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012

Long-term DNEL Assessment Factors (Inhalation)
Assessment Factor	Worker
Interspecies	2.5 (for systemic effects) (no allometric scaling factor applied)
Intraspecies	5 (for worker)
Exposure duration	4 (sub-acute to chronic)
Issues related to reliability of the dose-response	1
Issues related to completeness and consistency of the available data	1
Overall AF	50

DNEL Worker long-term-systemic via inhalation route = 44 / 50 = 0.88 mg/m³

DNEL Worker long-term Inhalation-local

The test item is not classified for eye or respiratory irritation according to CLP. Therefore, no hazard has been identified for local effects via the inhalation route, neither for short-term nor for long-term exposure.

DNEL Worker long-term Dermal-systemic

Dose descriptor

A NOAEL of 50 mg/Kg bw/d will be used as the starting point.

Modification of dose descriptor

Note: Dermal absorption assumed not be higher than oral absorption, therefore no default factor (i.e. factor 1) introduced when performing oral-to-dermal extrapolation.

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012

Long-term DNEL Assessment Factors (Inhalation)
Assessment Factor	Worker
Interspecies	2.5 (for systemic effects) 4 (allometric scaling factor for rats)
Intraspecies	5 (for worker)
Exposure duration	4 (sub-acute to chronic)
Issues related to reliability of the dose-response	1
Issues related to completeness and consistency of the available data	1
Overall AF	200

DNEL Worker long-term-systemic via dermal route = 50 / 200 = 0.25 mg/Kg bw/day

DNEL Worker long-term Dermal-local

The test item is not classified for skin irritation according to Regulation (EC) No 1272/2008 (CLP). Thus, there is no hazard identified for dermal local effects. For further information, please refer to the discussion.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.22 mg/m³

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

21.74 mg/m³

Explanation for the modification of the dose descriptor starting point:

Modification of dose descriptor:

Converted oral NOAEL rat (in mg/Kg bw/day) into inhalation NOAEC human (in mg/m³) by using a default respiratory volume for the rat corresponding to the daily duration of human exposure, followed by a correction for differences in absorption between routes, and a correction for differences in inhalation absorption between rats and humans.

Corrected inhalatory NOAEC = oral NOAEL x (1 / sRV_rat) x (ABS_oral-rat/ ABS_inh-human)

= 50 mg/Kg bw/day x (1/1.15 m³/Kg bw/day) x (1/2)

= 21.74 mg/m³

Note: A default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) introduced in the case of oral-to-inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for differences in duration of exposure:

4

Justification:

The exposure duration of the OECD TG 422 study performed with the test item was up to 63 days for females and 29 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the assessment factor of 4.

AF for interspecies differences (allometric scaling):

1

Justification:

Default assessment factor of 1 applied – no Allometric scaling factor for rats compared to humans (page 62, Example B3, of the ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for other interspecies differences:

2.5

Justification:

Additional factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for intraspecies differences:

10

Justification:

For general population, as standard procedure for threshold effects, a default assessment factor of 10 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012)

AF for the quality of the whole database:

1

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.125 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

400

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Modification of dose descriptor:

Converted oral NOAEL rat (in mg/Kg bw/day) into dermal N(L)OAEL rat (in mg/Kg bw/day) by correcting for differences in absorption between routes as well as for differences in dermal absorption between rats and humans.

Corrected dermal NOAEL = oral NOAEL x (ABS_oral-rat/ ABS_dermal-rat) x (ABS_dermal-rat/ ABS_dermal-human)

= 50 mg/Kg bw/day x (ABS_oral-rat/ ABS_dermal-human)

= 50 mg/Kg bw/day x (1/1)

Corrected dermal NOAEL = 50 mg/Kg bw/day

Note: Dermal absorption assumed not be higher than oral absorption, therefore no default factor (i.e. factor 1) introduced when performing oral-to-dermal extrapolation (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for differences in duration of exposure:

4

Justification:

The exposure duration of the OECD TG 422 study performed with the test item was up to 63 days for females and 29 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the assessment factor of 4.

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling factor for rats compared to humans (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for other interspecies differences:

2.5

Justification:

Additional factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for intraspecies differences:

10

Justification:

For general population, as standard procedure for threshold effects, a default assessment factor of 10 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for the quality of the whole database:

1

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.125 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

400

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Modification of dose descriptor:

No modification necessary (assuming 100% absorption for both routes in both species)

Corrected Oral NOAEL= 50 mg/Kg bw/day

Note: 100% absorption for both routes in both species assumed (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for differences in duration of exposure:

4

Justification:

The exposure duration of the OECD TG 422 study performed with the test item was up to 63 days for females and 29 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the assessment factor of 4.

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling factor for rats compared to humans (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for other interspecies differences:

2.5

Justification:

Additional factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for intraspecies differences:

10

Justification:

For general population, as standard procedure for threshold effects, a default assessment factor of 10 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for the quality of the whole database:

1

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Acute toxicity

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not required if no acute toxicity hazard leading to classification has been identified. p-Cymene is not acutely toxic following oral or dermal exposure (LD₅₀>2000 mg/Kg bw). No DNELs for acute toxicity are therefore necessary.

Irritation

p-Cymene is not considered a primary skin or eye irritant and is thus not classified under EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. Thus, for local effects there is no hazard identified.

Sensitisation

The sensitisation potential of p-Cymene is well understood and comprises results from a local lymph node assays, a human maximisation test, and a guinea pig open epicutaneous test. The results consistently showed thatp-Cymene is not a skin sensitizer.